chr1-47251846-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001048166.1(STIL):c.3157G>A(p.Gly1053Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000097 in 1,607,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

STIL
NM_001048166.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.61

Publications

2 publications found

Variant links:

Genes affected

STIL (HGNC:10879): (STIL centriolar assembly protein) This gene encodes a cytoplasmic protein implicated in regulation of the mitotic spindle checkpoint, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. The protein is phosphorylated in mitosis and in response to activation of the spindle checkpoint, and disappears when cells transition to G1 phase. It interacts with a mitotic regulator, and its expression is required to efficiently activate the spindle checkpoint. It is proposed to regulate Cdc2 kinase activity during spindle checkpoint arrest. Chromosomal deletions that fuse this gene and the adjacent locus commonly occur in T cell leukemias, and are thought to arise through illegitimate V-(D)-J recombination events. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

STIL Gene-Disease associations (from GenCC):

autosomal recessive primary microcephaly
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
microcephaly 7, primary, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
holoprosencephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

STIL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13432622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STIL	NM_001048166.1 link	c.3157G>A	p.Gly1053Ser	missense_variant	Exon 17 of 17	ENST00000371877.8	NP_001041631.1	Q15468-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STIL	ENST00000371877.8 link	c.3157G>A	p.Gly1053Ser	missense_variant	Exon 17 of 17	1	NM_001048166.1	ENSP00000360944.3		Q15468-2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000739

AC:

AN:

243496

AF XY:

0.000114

show subpopulations

Gnomad AFR exome

AF:

0.0000622

Gnomad AMR exome

AF:

0.0000302

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000902

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000941

AC:

137

AN:

1455218

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

723560

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33252

American (AMR)

AF:

0.0000458

AC:

AN:

43660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25634

East Asian (EAS)

AF:

0.000101

AC:

AN:

39666

South Asian (SAS)

AF:

0.000177

AC:

AN:

84848

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.0000992

AC:

110

AN:

1109190

Other (OTH)

AF:

0.0000832

AC:

AN:

60082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000125

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41566

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly 7, primary, autosomal recessive

Uncertain:1

Apr 17, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Apr 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with STIL-related conditions. This variant is present in population databases (rs201354921, gnomAD 0.02%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1052 of the STIL protein (p.Gly1052Ser). ClinVar contains an entry for this variant (Variation ID: 160062). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STIL protein function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;.;.;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;.;.;.

PhyloP100

3.6

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.5

N;D;N;N

REVEL

Benign

0.072

Sift

Benign

0.35

T;D;T;T

Sift4G

Benign

0.47

T;T;T;T

Polyphen

0.98

D;.;D;D

Vest4

0.27

MutPred

0.23

Loss of glycosylation at S1051 (P = 0.0602);.;.;.;

MVP

0.70

MPC

0.40

ClinPred

0.16

GERP RS

4.8

Varity_R

0.090

gMVP

0.42

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over